Primary liver cancer, hepatocellular carcinoma (HCC) is 1 of the most common forms of cancer worldwide, causing an estimated 1.3M deaths annually (Venook, 1994). Because HCC is often detected only in late stages, it is 1 of the most lethal forms of cancer, with average survival after onset of initial symptoms of 3-4 months. New forms of therapy are desperately needed. Our approach is based on work indicating that liver cancer cells are auxotrophic for arginine. Degradation or elimination of arginine selectively kills HCC cell lines and prolongs life in rodent cancer models. A recent Phase I/II cohort dose-escalation study of 19 HCC patients treated with PEGylated arginine deiminase [cloned from Mycoplasma hominis] demonstrates proof-of-concept in humans (Izzo et al., 2004). In this study, 2 patients had a CR, 7 had a PR, 7 had stable disease and 3 progressed. These encouraging results provide the rationale for the development of an improved therapeutic modality. We propose to use a human enzyme to eliminate problems due to immunogenicity and to target this enzyme directly to liver cancer cells using a proprietary human monoclonal antibody developed in our laboratory. In phase I, we will construct and test the novel fusion protein ("HEPzyme"). In phase II, we will carry out human tumor xenograft models and preclinical pharm-tox studies in preparation for an IND. We expect this work to result in a novel proprietary therapy for HCC likely to synergize with other therapeutic modalities. Liver cancer is 1 of the most common and lethal forms of cancer worldwide. This project will develop a novel form of enzyme therapy that will specifically target liver cancer and kill cancer cells with a unique mechanism of action. [unreadable] [unreadable] [unreadable]